1. Field of the Invention
The present invention relates to pharmaceutical compositions. In particular, the present invention relates to compositions comprising cyclodextrins.
2. Description of the Related Art
Cyclodextrins are cyclic oligosaccharides containing 6, 7, or 8 glucopyranose units, referred to as α-cyclodextrin (structure depicted below), β-cyclodextrin, or γ-cyclodextrin respectively, which are often used in pharmaceutical formulations. Cyclodextrins have a hydrophilic exterior, which makes them water-soluble, and a hydrophobic interior which forms a cavity. In an aqueous environment, hydrophobic portions of molecules often enter the hydrophobic cavity of cyclodextrin to form inclusion compounds. Although inclusion compounds are often formed between cyclodextrins and hydrophobic molecules, cyclodextrins are also capable of other types of nonbonding interactions with molecules that are not inside the hydrophobic cavity. Cyclodextrins have three free hydroxyl groups for each glucopyranose unit, or 18 hydroxyl groups on α-cyclodextrin, 21 hydroxyl groups on β-cyclodextrin, and 24 hydroxyl groups on γ-cyclodextrin. One or more of these hydroxyl groups can be reacted with any of a number of reagents to form a large variety of cyclodextrin derivatives. Some of the more common derivatives of cyclodextrin are hydroxypropyl ethers, sulfonates, and sulfoalkylethers.
In pharmaceutical formulations, cyclodextrins and cyclodextrin derivatives are often used to improve the solubility of a drug. While inclusion compounds are involved in many cases of enhanced solubility, other interactions between cyclodextrins and insoluble compounds can also improve solubility. As mentioned, the use of cyclodextrins in pharmaceutical compositions is well known in the art. For example, U.S. Pat. No. 6,407,079 teaches the use of β-cyclodextrin derivatives to form inclusion compounds that improve the solubility of the drug.
Cyclodextrin derivatives have been demonstrated to be useful in solubilizing lipophilic or water-insoluble therapeutic agents or drugs. For example, U.S. Pat. No. 5,472,954 discloses the use of hydroxypropylmethylcellulose and hydroxypropyl cyclodextrins to solubilize hydrocortisone. The use of cyclodextrin and cyclodextrin derivatives in ophthalmic formulations is also known. For example, U.S. 2002/0198174 discloses a composition comprising “cyclodextrin”, “prednisolone acetate”, and “PHMB (1 ppm)” among other components, and EP 0435682 A2 teaches the use of cyclodextrins in ophthalmic compositions with prostaglandins to treat ocular hypertension.
Antimicrobial preservation of cyclodextrin-containing formulations can present special problems. For example, Loftsson et al., Drug Development and Industrial Pharmacy, 18 (13), 1477–1484 (1992), have investigated interactions between several commonly used preservatives and 2-hydroxypropyl-β-cyclodextrin (HPβCD). Loftsson et al. reported that the antimicrobial activity of the preservative can be reduced by the formation of preservative-cyclodextrin inclusion complexes, specifically chlorobutanol, methylparaben, propylparaben, had significantly reduced preservative activity for a number of pathogens, and it was shown that chlorobutanol reduces the solubilizing effects of HPβCD on hydrocortisone, prednisolone, and triamcinolone. However, benzalkonium chloride and chlorhexidine gluconate did possess preservative activity in HPβCD solutions. Additionally, Simpson, FEMS Microbiology Letters, 90, 197–200 (1992), reported that cyclodextrins can inactivate the antimicrobial activity of certain quaternary ammonium compounds. See also, Miyajima et al., Chem. Pharm. Bull., 35(1), 389–393 (1987), regarding the interaction of short-chain alkylammonium salts with cyclodextrins in aqueous solutions, which concluded that α-, β-, and γ-cyclodextrins form complexes with alkylammonium salts having alkyl groups longer than n-butyl, n-hexyl, and n-decyl, respectively.
JP 60149530 A (Takeda Chem. Ind., Ltd.) discloses aqueous compositions of a principal agent and a cyclodextrin where the compositions contain as a preservative a chlorhexidine derivative of the formula where A is [independently] (un)substituted phenyl; n is 3–9; and the polymethylene chain may be interrupted by an oxygen atom or an aromatic ring.
JP 01016728 A (Santen Seiyaku KK) discloses antiseptic aqueous preparations containing a drug, a cyclodextrin and a cationic surfactant as a preservative. By adding a cyclodextrin or cyclodextrin derivative, cationic surfactants commonly incompatible with certain drugs can be combined. Disclosed cationic surfactants are benzalkonium chloride, benzethonium chloride or chlorohexidine gluconate. Disclosed drugs include sodium hyaluronate, pilocarpine hydrochloride, lysosyme chloride, Na2 chondroitin sulfate, glycyrrhetinate, pirenoxine, sodium chromoglycate, and dimethylisopropylazulene sodium sulfate.
JP 6016547 A (Wakamoto Pharm. Co. Ltd.) discloses eye drop compositions containing diclofenac sodium and a water soluble cyclodextrin compound. The reference also discloses that these compositions can be preserved using benzalkonium chloride, benzethonium chloride and chlorhexidine gluconate as cationic surfactants; methylparaben, ethylparaben, propylparaben and butylparaben as parabens; and phenylethyl alcohol and benzyl alcohol as alcohols.
U.S. Pat. No. 5,998,488 discloses “The ophthalmic composition of the invention contains (1) an antimicrobial preservative having a cationic group, (2) a cyclodextrin, (3) ethylenediaminetetraacetic acid or a salt thereof, and (4) boric acid and/or borax as essential components.” This patent also discloses that “The antimicrobial preservative having a cationic group used herein may be selected from well-known antimicrobial preservatives, for example, quaternary ammonium salts such as benzalkonium chloride, benzethonium chloride, cetyldimethylbenzylammonium chloride, domiphen bromide, 3-(trimethoxysilyl)propyldimethyloctadecylammonium chloride, stearyldimethylbenzylammonium chloride, stearyltolylmethyl-ammonium chloride, distearyldimethylammonium chloride, stearylpentaethoxyammonium chloride, cetylpyridinium chloride, cetylpyridinium bromide, and lauroylisoquinolium bromide; and guanidines such as chlorohexidine hydrochloride, chlorohexidine gluconate, dodecylguanidine hydrochloride, polyhexmethylenebiguanidine hydrochloride, and 6-acetoxy-2,4-dimethylmetadioxane.” However, the patent further states “benzalkonium chloride is most effective and preferable.”
In citing the foregoing references, and other references cited herein, applications make no admission as to whether any of said references constitutes prior art. Rather, the determination of what constitutes prior art is a legal exercise made on the basis of the dates said references were made available to the public, the authors or inventors of said references, and the effective filing date of the disclosure made herein.